The European Clinical Trials Facilitation Group published a Q&A document in 2017 addressing the requirements for Reference Safety Information (RSI) for medicinal products being used in clinical trials. The RSI is used for expectedness assessment for adverse reactions reported in clinical trials for two purposes:
- To help identify SUSARs which are subject to expedited reporting
- To categorise events reported in the Development Safety Update Report (DSUR) which is sent annually to regulators and ethics committees
The requirements outlined in this document become mandatory from January 2019 and so it is important for those involved in any aspect of ADR reporting to be aware of them.
What should be included in the RSI.
- There should be a specific section in the Investigators Brochure entitled “Reference safety information for assessment of expectedness of serious adverse reactions”and this section should be the basis for expectedness assessment, not the general safety information section. An event can only be considered expected if it appears at the same frequency, specificity and intensity in the RSI section in the IB. For licensed products the Summary of Product Characteristics (SmPC) can be used as the RSI if the product is used within the terms of its marketing authorisation and the SmPC is identified as the source of the RSI in the Clinical Trials Authorisation (CTA) application cover letter.
- The “RSI is a list of expected serious adverse reactions, which are classified using Preferred Terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA)”
- Expected events should only be included in the RSI if they are Serious and meet the following criteria:
- There is reasonable evidence of a causal relationship to the IMP after through review by the sponsor
- The event has been reported as a suspected serious adverse reaction more than once
- The event has been observed with this product. You can’t include events which might be anticipated from the pharmacology of the product or the product class.
- There’s a section on fatal and life-threatening events, which, being honest, I find a little confusing. However my reading of it is that generally speaking there should be no fatal or life-threatening SARs listed in the RSI. The argument is that sponsors should not expect a product to cause fatal or life-threatening reactions unless there is a robust risk-benefit analysis to support this. This means that fatal and life-threatening SARs will usually be unexpected even if fatal or life-threatening events have been seen previously. For a marketed product a fatal or life-threatening event can be considered expected if the event is listed in the SmPC, but for unlicensed products there should never be fatal or life-threatening events in the RSI.
- What about events where the causality assessment is unlikely or possible? The advice is as follows: “An adverse reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship between a medicinal product and an occurrence is suspected. Thus in a clinical trial setting, a causal relationship to the IMP is either considered to be suspected or not for each individual adverse event which occurs. If an investigator uses the WHO classification categories of causality when assessing causality, ‘highly probable’, ‘probable’, ‘possible’ should be regarded as related by the sponsor, while ‘unlikely’ and ‘not’ may be considered to be not related.”
Updates and Assessing Expectedness
There is additional guidance about updating the RSI and about determining expectedness for expedited reporting and the DSUR, and I strongly recommend that you visit the links below and read the document for yourself.
CTFG Q&A document implementation note: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2018_03_CTFG_RSI_Q_A_Covernote.pdf